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9. SARS Treatment
Loletta
Kit-Ying SO (Correspondence) The treatment of coronavirus-associated SARS has been evolving and so far there is no consensus on an optimal regimen. This chapter reviews the diverse treatment experience and controversies to date, and aims to consolidate our current knowledge and prepare for a possible resurgence of the disease. Treatment strategies for SARS were first developed on theoretical bases and from clinical observations and inferences. Prospective randomized controlled treatment trials were understandably lacking during the first epidemic of this novel disease. The mainstream therapeutic interventions for SARS involve broad-spectrum antibiotics and supportive care, as well as antiviral agents and immunomodulatory therapy. Assisted ventilation in a non-invasive or invasive form would be instituted in SARS patients complicated by respiratory failure. Anti-bacterial agents are routinely prescribed for SARS because its presenting features are non-specific and rapid laboratory tests that can reliably diagnose the SARS-CoV virus in the first few days of infection are not yet available. Appropriate empirical antibiotics are thus necessary to cover against common respiratory pathogens as per national or local treatment guidelines for community-acquired or nosocomial pneumonia (Niederman et al 2001). Upon exclusion of other pathogens, antibiotic therapy can be withdrawn. In addition to their antibacterial effects, some antibiotics are known to have immunomodulatory properties, notably the quinolones (Dalhoff & Shalit 2003) and macrolides (Labro & Abdelghaffar 2001). Their effect on the course of SARS is undetermined. SARS can present with a spectrum of disease severity. A minority of patients with a mild illness recover either without any specific form of treatment or on antibiotic therapy alone (Li G et al 2003; So et al 2003). Various antiviral agents were prescribed empirically from the outset of the epidemic and their use was continued despite lack of evidence about their effectiveness. With the discovery of the SARS-CoV as the etiologic agent, scientific institutions worldwide have been vigorously identifying or developing an efficacious antiviral agent. Intensive in vitro susceptibility tests are underway. Ribavirin, a nucleoside analog, was widely chosen as an empirical therapy for SARS because of its broad-spectrum antiviral activity against many DNA and RNA viruses. It was commonly used with corticosteroids and has since become the most frequently administered antiviral agent for SARS (Peiris et al 2003a, 2003b; So et al 2003; Tsang KW et al 2003; Poutanen et al 2003; Chan-Yeung & Yu 2003; Koren et al 2003; Lee et al 2003; Booth et al 2003; Tsang & Lam 2003; Chan et al 2003; Tsui et al 2003; Ho JC et al 2003). The use of ribavirin has attracted a lot of criticism due to its unproven efficacy and undue side effects (Cyranoski 2003). Ribavirin at non-toxic concentrations has no direct in vitro activity against SARS-CoV (Huggins 2003; Cinatl et al 2003a; Health Canada July 2, 2003). Clinical experience so far, including quantitative reverse transcriptase polymerase chain reaction (RT-PCR) monitoring the nasopharyngeal viral load, has also not been able to suggest any substantial in vivo antiviral effect from this drug (Peiris et al 2003b). It is still a moot point as to whether or not the immunomodulatory actions of ribavirin, as found in other conditions (Ning et al 1998; Hultgren et al 1998), could also play a role in the treatment of SARS (Peiris et al 2003b; Lau & So 2003). The prevalence of side effects from ribavirin is dose-related. High doses often result in more adverse effects, such as hemolytic anemia, elevated transaminase levels and bradycardia (Booth et al 2003). However, lower doses of ribavirin did not result in clinically significant adverse effects (So et al 2003). Side effects have also been observed more frequently in the elderly (Kong et al 2003). Oseltamivir phosphate (Tamiflu®, Roche Laboratories Inc., USA) is a neuraminidase inhibitor for the treatment of both influenza A and B viruses. It was commonly prescribed together with other forms of therapy to SARS patients in some Chinese centers. Since there is no evidence that this drug has any efficacy against SARS-CoV, it is generally not a recommended treatment apart from in its role as an empirical therapy to cover possible influenza. Lopinavir-ritonavir co-formulation (Kaletra®, Abbott Laboratories, USA) is a protease inhibitor preparation used to treat human immunodeficiency virus (HIV) infection. It has been used in combination with ribavirin in several Hong Kong hospitals, in the hope that it may inhibit the coronaviral proteases, thus blocking the processing of the viral replicase polyprotein and preventing the replication of viral RNA. Preliminary results suggest that the addition of lopinavir-ritonavir to the contemporary use of ribavirin and corticosteroids might reduce intubation and mortality rates, especially when administered early (Sung 2003). It thus appears worthwhile to conduct controlled studies on this promising class of drugs. Interferons are a family of cytokines important in the cellular immune response. They are classified into type I (interferon α and β , sharing components of the same receptor) and type II (interferon γ which binds to a separate receptor system) with different antiviral potentials and immunomodulatory activities. So far, the use of interferons in the treatment of SARS has been limited to interferon α , as reported from China (Zhao Z et al 2003; Wu et al 2003; Gao et al 2003) and Canada (Loutfy et al 2003). The Chinese experiences were mostly in combining the use of interferons with immunoglobulins or thymosin, from which the efficacy could not be ascertained. Faster recovery was observed anecdotally in the small Canadian series using interferon alfacon-1 (Infergen®, InterMune Inc., USA), also known as consensus interferon, which shares 88% homology with interferon α -2b and about 30% homology with interferon β . In vitro testing of recombinant interferons against SARS-CoV was recently carried out in Germany (Cinatl et al 2003b) using interferon α -2b (Intron A®, Essex Pharma), interferon β -1b (Betaferon®, Schering AG) and interferon γ -1b (Imukin®, Boehringer Ingelheim). Interferon β was found to be far more potent than interferon α or γ , and remained effective after viral infection. Although interferon α could also effectively inhibit SARS-CoV replication in cell cultures, its selectivity index was 50-90 times lower than that of interferon β . These in vitro results suggested that interferon β is promising and should be the interferon of choice in future treatment trials. Human gamma immunoglobulins were used in some hospitals in China and Hong Kong (Wu et al 2003; Zhao Z et al 2003). In particular, an IgM-enriched immunoglobulin product (Pentaglobin®, Biotest Pharma GmbH, Germany) was tried in selected SARS patients who were deteriorating despite treatment (Tsang & Lam 2003). However, as there was often concomitant use of other therapies such as corticosteroids, their effectiveness in SARS remains uncertain. Convalescent plasma, collected from recovered patients, was also an experimental treatment tried in Hong Kong. It is believed that the neutralizing immunoglobulins in convalescent plasma can curb increases in the viral load. Preliminary experience of its use in a small number of patients suggests some clinical benefits and requires further evaluation (Wong et al 2003). In China, traditional herbal medicine has been frequently used in conjunction with Western medicine to treat SARS, and is believed to be effective (Zhong & Zeng 2003; Xiao et al 2003; Lin L et al 2003; Zhao CH et al 2003). Recently, glycyrrhizin, an active component derived from liquorice roots, was tested against SARS-CoV in vitro (Cinatl et al 2003a). It has previously been used in the treatment of HIV and hepatitis C virus infections, and was found to be relatively non-toxic with infrequent side effects (e.g. hypertension; hypokalemia). In Vero cell cultures, it could inhibit the adsorption, penetration and replication of SARS-CoV, and was most effective when administered both during and after viral adsorption. It has been postulated that the mechanisms are mediated through the nitrous oxide pathway (Cinatl et al 2003a). However, as glycyrrhizin can only act against SARS-CoV at very high concentrations, its clinical dosing and utility remain uncertain. It could perhaps be explored as an adjunct therapy for SARS, or continued as an ingredient or base in herbal preparations. The rationale for using immunomodulatory therapy in SARS is based on the fact that acute infections in general can stimulate the release of proinflammatory cytokines. In SARS, there may be an excessive host response or cytokine dysregulation. This hypothesis may be substantiated from the observation that clinical deterioration can paradoxically occur despite a fall in the viral load as IgG seroconversion takes place (Peiris et al 2003b), as well as from autopsy findings which demonstrate a prominent increase in alveolar macrophages with hemophagocytosis (Nicholls et al 2003). A tri-phasic model of pathogenesis comprising viral replicative, immune hyperactive and pulmonary destructive phases was thereafter proposed (Peiris et al 2003b; Sung 2003). Intuitively, immunomodulatory therapy carefully applied during the hyper-immune phase may be an important treatment component in SARS. Corticosteroids have been the mainstay of immunomodulatory therapy for SARS. Their timely use often led to early improvement in terms of subsidence of fever, resolution of radiographic infiltrates and better oxygenation, as described in many Chinese and Hong Kong reports (Zhong & Zeng 2003; Xiao et al 2003; Wu et al 2003; Zhao Z et al 2003; Meng et al 2003; So et al 2003; Lau & So 2003; Lee et al 2003; Tsang & Lam 2003; Ho JC et al 2003). However, there is much scepticism and controversy about the use of corticosteroids, centering on their effectiveness, adverse immunosuppressive effects and impact on final patient outcomes. An early Singaporean report on five patients on mechanical ventilation indicated that corticosteroids showed no benefits (Hsu et al 2003). A retrospective series of over 320 patients from a regional hospital in Hong Kong concluded that two-thirds progressed after early use of ribavirin and corticosteroids, but only about half of these subsequently responded to pulsed doses of methylprednisolone (Tsui et al 2003). A cohort study also noted that about 80% of patients had recurrence of fever and radiological worsening (Peiris et al 2003b). This contrasted with another paper which described four patient stereotypes for pulsed methylprednisolone therapy, namely the good responder, good responder with early relapse, fair responder and poor responder. The good responders were the most common group (Tsang & Lam 2003). There was also a comparative study showing the efficacy and safety of pulsed methylprednisolone as an initial therapy compared with a lower dosage regimen (Ho JC et al 2003). On the contrary, pulsed methylprednisolone was identified as a major independent predictor for mortality (Tsang OTY et al 2003). The inconsistencies of treatment outcomes in SARS (or other illnesses) could be due to differences in the timing, dosing and duration of corticosteroid use (Lau & So 2003; Meduri & Chrousos 1998). The following points have been emphasized (So et al 2003; Lau & So 2003):
The ultimate aim should theoretically be to strike an optimal immune balance so that the patient can mount a sufficient adaptive immune response to eradicate the virus, but without the sequelae of irreversible lung damage from immune over-reactivity. A published protocol (Appendix 1) based on the above rationale was reported to have achieved satisfactory clinical outcomes (So et al 2003; Lau & So 2003). Although corticosteroids can be beneficial, their use is not without risk. Profound immunosuppression, resulting from needlessly high doses or protracted usage of corticosteroids, not only facilitates coronaviral replication in the absence of an effective antiviral agent, but also invites bacterial sepsis and opportunistic infections. There has been one report of a SARS patient who died from systemic fungal infection (Wang et al 2003). The common phenomenon of "radiological lag" (radiological resolution lagging behind clinical improvement) must be recognized. As long as the patient remains clinically stable, it is likely that an optimal immune balance has been reached, and most radiological infiltrates will resolve gradually on a diminishing course of corticosteroids over 2-3 weeks. No additional corticosteroids are necessary to hasten radiological resolution under such circumstances (Lau & So 2003; Yao et al 2003). Radiographic abnormalities arising from a superimposed bacterial pneumonia must also be differentiated from the progressive immunopathological lung damage of SARS, since the latter would result in adding further corticosteroids. As superimposing infections add to the morbidity and mortality and offset the beneficial effects of corticosteroids in SARS, it is of vital importance that strict control of hyperglycemia during corticosteroid administration is implemented to reduce the chance of septic complications (Van den Berghe et al 2001) and measures are taken to prevent ventilator-associated pneumonia (Collard et al 2003). Successful control of superimposing infections also demands a judicious use of empirical and culture-directed antimicrobials. In summary, corticosteroids must not be indiscriminately prescribed for SARS, but should only be used according to the above principles and by exercising good clinical judgment. Thymosin alpha 1 (Zadaxin®, SciClone Pharmaceuticals Inc., USA) is used in the treatment of chronic viral hepatitis B and C, and has also been administered to SARS patients in some Chinese hospitals (Zhao Z et al 2003; Gao et al 2003). It is a relatively safe product and may augment T-cell function. The role and effectiveness of this agent in SARS has not yet been determined. Other immunomodulatory agents in anecdotal use included tumor necrosis factor blocking agents, namely etanercept (Enbrel®, Immunex Corporation, USA) and infliximab (Remicade®, Centocor Inc., USA), and some other compounds like cyclophosphamide, azathioprine, cyclosporin and thalidomide. Despite treatment efforts, some SARS patients still develop acute hypoxemic respiratory failure. According to the current literature, 20-30% of SARS warranted admission into intensive care units, and 10-20% eventually required intubation and mechanical ventilation. The initial management of SARS-related respiratory failure is oxygen supplementation. If the oxygen saturation remains low or dyspnea persists, assisted ventilation, either through non-invasive or invasive means, has to be considered. Non-invasive ventilation (NIV) is instituted via a face or nasal mask, as distinguished from invasive ventilation which necessitates endotracheal intubation. It is a valuable treatment for acute respiratory failure of various causes, and can avoid complications associated with intubation and invasive ventilation (Baudouin et al 2002; Peter et al 2002). Its application in SARS may be of particular benefit since SARS patients are frequently treated with high dose corticosteroids, which predispose them to infections including ventilator-associated pneumonia. NIV, as either continuous positive airway pressure (CPAP) or bi-level pressure support, was commonly employed in many Chinese hospitals (Zhong & Zeng 2003; Luo & Qian 2003; Liu et al 2003; Xiao et al 2003; Zhao Z et al 2003; Wu et al 2003; Li H et al 2003) and in one hospital in Hong Kong (So et al 2003). Its use can improve oxygenation and tachypnea within an hour, and this may help to prevent adding further corticosteroids for respiratory failure (Liu et al 2003). In general, NIV was found to be able to avoid intubation and invasive ventilation in up to two-thirds of SARS patients with deterioration (Xiao et al 2003; Zhao Z et al 2003; Unpublished data from Hong Kong). NIV can be given using a CPAP of 4-10 cm H2O or bi-level pressure support with an inspiratory positive airway pressure (IPAP) of <10 cm H2O and an expiratory positive airway pressure (EPAP) of 4-6 cm H2O. Contrary to the scenarios for non-SARS-related acute respiratory distress syndrome, higher pressures were generally not necessary and should be avoided whenever possible, because not only was there usually no additional clinical improvement observed, but it can also add to the risk of pneumothorax and pneumomediastinum. The latter conditions are known complications of SARS, even without assisted positive pressure ventilation (Peiris et al 2003b). Although NIV can improve patient outcome, the infective risks associated with aerosol generation have hampered its use in many hospitals. Nevertheless, centers with experience have reported the use of NIV to be safe, if the necessary precautions are taken (Li H et al 2003; Zhao Z et al 2003; Unpublished data from Hong Kong). In addition to the recommended standard infection control measures for aerosol-generating procedures (Centers for Disease Prevention and Control [CDC] May 6, September 23, 2003; World Health Organization [WHO] April 24, 2003), the use of exhalation ports which generate round-the-tube laminar airflow (e.g. Whisper Swivel II, Respironics Inc., USA) and viral-bacterial filters interposed between the mask and exhalation port may further reduce the infective risk. Invasive mechanical ventilation Patients with SARS-related respiratory failure who continue to deteriorate while on NIV, or in whom NIV is contraindicated, should be promptly intubated and mechanically ventilated. The actual endotracheal intubation procedure bears a high infective risk and healthcare workers must strictly adhere to all infection control measures. To minimize the risk, the procedure is best performed by highly skilled personnel (Lapinsky & Hawryluck 2003) using rapid sequence induction. Other approaches like a "modified awake" intubation technique and elective intubation upon recognizing signs of imminent need for airway management have been recommended (Cooper et al 2003). Most centers (Lew et al 2003; Gomersall & Joynt 2003) used ventilation method and settings with reference to the strategies for acute respiratory distress syndrome (ARDS) (The ARDS network 2000). Both pressure and volume control ventilation can be employed. The tidal volume should be kept low at 5-6 ml per Kg of the predicted body weight, and plateau pressures be kept less than 30 cm H2O. Positive end-expiratory pressure (PEEP) should also be titrated to as low as possible to maintain the oxygenation, since a high rate (34%) of barotraumas have been reported (Fowler et al 2003). Mechanically ventilated patients should be adequately sedated and a short-term neuromuscular blockade may be required for permissive hypercapnia. In this SARS epidemic, which eventually involved 8098 probable cases worldwide, the overall case-fatality ratio has been updated to 9.6%. Significant regional differences were seen. China had the greatest number (5327) of cases, but its case-fatality ratio was reported as being only 7%. Hong Kong came second with 1755 cases, of whom 17% died. Taiwan, Canada and Singapore followed, and their ratios were 11%, 17%, and 14% respectively (WHO September 23, 2003). Age-stratified ratios were estimated to be <1% in patients < 24 years old, 6% in 25-44 years old, 15% in 45-64 years old, and >50% in elderly > 65 years old (WHO May 7, 2003). The estimates in Hong Kong were 13% in patients <60 years old, and 43% in those > 60 (Donnelly et al 2003). In addition to age, death rates may be affected by other patient factors such as genetic predispositions, the immune status, pre-existing co-morbidities and cardiopulmonary reserve, and by the disease severity which depends theoretically on the viral strain's virulence, viral load and magnitude of the host's immune response. The rates may also be related to other factors such as case selection and volume, facilities and manpower, treatment strategies and regimens. A multi-center study comparing four treatment regimens in Guangzhou, China, found that a regimen (Appendix 2) of early use of higher dose corticosteroids, coupled with nasal continuous positive airway pressure (CPAP) ventilation, produced the least mortality. All 60 clinically-defined SARS patients (mean age 30.5 years) treated with this regimen survived, 40% of them used CPAP and none required mechanical ventilation. Only a small number of deaths were recorded out of a further 160 cases treated with the same regimen (Zhao Z et al 2003). Favorable protocol-driven treatment outcomes were also reported from a center in Hong Kong. The protocol (Appendix 1) was applied to 88 consecutively admitted SARS patients (mean age 42), of whom 97% were laboratory-proven cases. The overall mortality was 3.4% (3/88) occurring in patients aged > 65 only, out of which two died from co-morbidities instead. 24% required intensive care unit admission, 14% received non-invasive ventilation (bi-level pressure support) and 10% invasive mechanical ventilation. High-resolution computed tomography performed 50 days after the commencement of treatment showed that most survivors did not have clinically significant lung scarring, and none required any form of pulmonary rehabilitation (Lau & So 2003). Based on the treatment experiences of the above and other centers with similar outcomes, suffice it to say that SARS may not be a disease of high mortality, at least in non-elderly patients. Even though a substantial portion may require a period of assisted ventilation, the mortality rate could be kept down to just a few percent by using appropriate management and therapeutic strategies. We have gained much experience in the treatment of SARS. Without being complacent, scientists and clinicians alike are striving for more effective treatment aiming to lower mortality and transmission rates as much as possible. This can only be achieved together with an increased understanding of the viral structure and processes (Holmes 2003; Thiel et al 2003) and by defining the potential targets for drug and vaccine development. The development of vaccines and new drugs for human use usually take many years. To expedite the development, the collaborative efforts around the world that unraveled the etiologic agent of SARS will be continued. Previous knowledge obtained from the HIV may give us a lead (Ho D 2003; Kliger & Levanon 2003; De Groot 2003), as well as the information known about the existing vaccines for animal coronaviruses (Clarke 2003). Three-dimensional computer modeling of key viral proteins may also facilitate the search and design of antivirals (Anand et al 2003). On the other hand, massive random screening and targeted searching of potential compounds by various institutions have already tested hundreds of thousands of compounds in vitro, and have had several hits which could be targets for further research (Abbott 2003). In addition to the antiviral studies, research on the gene expression profiles (Cameron et al 2003; Lin M et al 2003) and the disease immune profiles (Li Z et al 2003; Beijing Group of National Research Project for SARS 2003) are in progress. In the future, they may facilitate the diagnosis, monitoring and tailoring of specific immunotherapies. While awaiting research breakthroughs, we have to rely on the existing treatment modalities, which have been overviewed in this chapter. It is envisaged that with the early use of efficacious antiviral agents singly or in combination, the necessity for high dose immunomodulatory therapy may be decreased. Well-conducted randomized controlled trials on a sufficient number of cases are necessary to clarify the effectiveness of and controversies surrounding existing treatment regimens; however, these may not be feasible since large-scale outbreak will hopefully never be seen again with our heightened preparedness. A standardized treatment protocol for adult SARS in Hong Kong From: So, et al. Lancet 2003;361:1615-6 (1) Antibacterial treatment
(2) Ribavirin and methylprednisolone Add combination treatment with ribavirin and methylprednisolone when:
Standard corticosteroid regimen for 21 days
Ribavirin regimen for 10-14 days
(3) Pulsed methylprednisolone
A treatment regimen for SARS in Guangzhou, China Extracted & modified from Zhao Z, et al. J Med Microbiol 2003; 52: 715-20
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